Metronidazole, 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole, has long been known as an effective drug to treat a variety of disorders, and is especially well known for the treatment of various protozoal diseases. As a topical therapy, metronidazole has also been shown to be useful in treating various skin disorders, including acne rosacea, bacterial ulcers, and perioral dermatitis. See, Borgman, U.S. Pat. No. 4,837,378. Metronidazole has been found to have an anti-inflammatory activity when used topically to treat dermatologic disorders. See, Czernielewski, et al., U.S. Pat. No. 5,849,776. Metronidazole may also be used as an intravaginal therapeutic agent for the treatment of bacterial vaginosis. See, Borgman, U.S. Pat. No. 5,536,743.
Compositions containing metronidazole for treatment of dermatologic disorders are available in cream, lotion and gel forms. One commercially available metronidazole cream product, NORITATE™ (Dermik Laboratories, Inc., Collegeville, Pa. 19426 USA) contains 1% metronidazole in which the insoluble drug is suspended in the opaque cream. A commercially available metronidazole gel product, METROGEL® (Galderma Laboratories, Inc. Fort Worth, Tex., 76133 USA), contains 0.75% metronidazole which is solubilized to produce a clear gel.
For the treatment of many dermatologic and mucosal disorders, it is often preferable to use a solubilized water-based formulation, such as a gel, rather than a cream, lotion or an ointment. Creams, lotions (typically oil in water emulsions) and ointments (typically petroleum jelly based compositions) are often comedogenic, acnegenic, or not cosmetically appealing to patients. Solubilized topical products are generally more bioavailable than products in which the active ingredient is insoluble.
The oil-based cream and ointment metronidazole formulations have an advantage over presently available gel-based formulations in that oil-based formulations may contain a concentration of metronidazole of 1%. Aqueous-based gel compositions are limited to a concentration of metronidazole of 0.75% because of the poor solubility of metronidazole in water.
Cyclodextrins have been shown to enhance the solubility of various drugs in aqueous solutions. An amphiphilic or lipophilic drug, such as metronidazole, is partially or completely enclosed within this cage structure, thereby increasing the solubility of the drug in aqueous media. Cyclodextrins have certain disadvantages, however, including expense, limitations of cyclodextrin solubility, incompatibility in certain vehicles, and potential for local and systemic toxicity.
Several authors have described the use of beta-cyclodextrin (BCD) in combination with metronidazole. Kata and Antal, Acta Pharmaceutica Hungarica, 54:116-122 (1984), disclose a marked increase in the rate of dissolution of metronidazole when dissolved in a solution containing BCD at 37° C. The stability of the BCD/metronidazole solutions is not addressed. Major problems with the use of BCD to solubilize drugs such as metronidazole is that BCD has a relatively low solubility in water and is a relatively inefficient solubilizer, particularly for lipophilic or amphiphilic drugs such as metronidazole. Additionally, cyclodextrins, such as BCD and its derivatives, are expensive and the drug formulations containing BCD as a solubilizing agent likewise become expensive. A need exists for a way to increase the solubility of drugs which requires a reduced concentration of BCD.
Solubility enhancing agents other than cyclodextrins have been described. Yie W. Chien, Journal of Parenteral Science and Technology, 38(1):32-36 (January 1984), discloses that niacinamide is a solubility enhancing agent that can increase the water solubility of MTZ. Chien further discloses that the water soluble vitamins ascorbic acid, and pyridoxine are solubility enhancing agents for aqueous solutions. Chien discloses that the solubility of metronidazole in water increases linearly with relation to the concentration of these water soluble vitamins in the solution. The Chien article is incorporated herein by reference. The prior art does not address the combination of cyclodextrins, such as BCD, with other solubility enhancing agents, such as niacinamide or other water soluble vitamins.